Process for preparation of steroidal hydroxy ketones



Patented Apr. 17, 1951 'PROCESS FOR mingmemw s'rE omAL; HYnRoxr KETONES.

RomeoEI WagnerQ' 'State College; -Pa.,-"and James A. Moore, Detroit,Miohi', assignor'sf to Parke,- {Davis & Company, Detroit, Mich.,acorporation of Michigan This invention relates to a process for thepreparation of steroids. Moreparticularly, it re- Ilates to thepreparation of steroids"which are "characterized by having acorticalsidej chain, that is, having hydroxyl or esterified hydroxylgroups at 'Cm'and C21 and'a keto groupflatCm. These20-keto-17,21-pregnandiol compounds can be represented by the followingformula:

" CHzOR CHs one where R is hydrogen or a lower aliphatic carboxylic acyl radical. ag

In accordance with; the invention the 2Q-keto- 17,21-pregnandiols ortheir corresponding acyl derivatives having the above formula areprepared by reacting -bromo-A -pregnen-21-ol compounds of the formula;

- omoR CH3 -Br with osmiumtet'rox'idawhere the R. groups have the samesignificance,asabove. The reaction is carried out below SO CIahdpreferably at about 20 to 30 C. Although the starting compoundscontaining R=hydrogen will undergo the reaction, the best yields areobtained using starting materials containing R=lower acyl radical. Thesolvent for the reaction is a lower' aliphatic ether or a cyclic ether.

The products of the invention are useful intermediates for thepreparation of other organic compounds and, in particular, for thepreparation of steroids similar in structure to those found in theadrenal cortex.

The following examples are illustrative:

Example 1 1500 mg. of osmium tetroxide are added to a solution of 1166mg. of 20-bromo-A -pregnen- 3(13) ,2'1-dio1 diacetate in 50 cc. ofether. A black g No Drawing. Application December 3,1949. t Serial No.131.057 I 3Claims. (01. 260-3974), 1f};

occurs after seven days.

precipitate forms after a few minutes. With the mixture-in a looselystoppered flask permitting slow evaporation of the solvent,crystallization The crystals are redissolved in more-ether and the blackosmium compound is separated by filtration, The filtrate is washed,with;ten portions of. aqueous sodium thiosulfate and thenwith water.Thedried ether layer is concentrated andthe residue is. dissolved inmethanqlycharcoaled and allowed to crystal- ,lize. 3 (B) ,17 (a)21-triol-20 one-3,2 1-diacetate melt at TheresultinaWhite needles ofpregnan- 149-151" C. The formula of this product is,

F 79. to

I Egrdmplc 2 1380 mg. of osmium tetroxide are added to a solution of 980mg'i of 20-bromo-A -pregnen- 3(p),21-dio1 in 40 cc. of ether. Afterstanding for seven days, the resulting solid which separates isdissolved in more 'ether and the mixture iSffilteredJ; The/filtrate iswashed withaqueous ,sodiurnf'thiosulfate and thenhwater. The ether layeris dried and concentrated. The resulting solid is crystalline and hasthe structure? onion CH3 0113 This solid is then dissolved in 5 cc. ofacetic anhydride and 5 cc. of pyridine. After standing for one hour thesolution is treated with 200 cc. of water. The oil is extracted withether, washed with dilute hydrochloric acid, water, dilute sodiumbicarbonate and water. The dried ether extract is concentrated and theresidue is recrystallized from methanol. The crystals of pregnan-3(p),17(a);21-trio1 3,21-diacetate melt at 150- tained in Example 1.

The 20-bromo-A -pregnen2l-o1 compounds used as starting materials in thepractice of the invention may be prepared by the methods described andclaimed in our copending application Serial No. 131,056, filed undereven date herewith. Said methods comprise the reduction of 20-bromo-A-pregnen-2l-oic acids or'esters of same with lithium aluminum hydride.The re: sulting steroid alcohol derivatives can be converted to thecarboxylic acid acyl derivatives by treatment with a lower aliphaticacid anhydride alone or in the presence of a basic substance.

The above mentioned ZO-brQmo-A -pregnen- 21-oic acids and esters may beprepared by the methods described and claimed in our copendingapplication Serial No. 131,055, filed under even date herewith. Saidmethods comprise reacting 17,21,21-tribrominated pregnanes with analkali metal hydroxide dissolved in a lower aliphatic alcohol and at apreferable reaction temperature of about 85-95 C. The resulting acidsare converted to the corresponding esters by treatment of the acids withadiazoalkane in an inert organic solvent.

The above mentioned 17,21,21-tribrominated pregnanes may be prepared bythe methods describedand claimed in our copending application Serial No.131,054, filed under even date herewith osmium tetroxide therebyobtaining a steroid having at ring D the structure,

C'HzOR where R is a member of the class consisting of H and loweraliphatic carboxylic acyl radicals.

2. Process which comprises reacting a steroid of formula,

4 with osmium tetroxide thereby obtaining a CHICK with osmium tetroxidethereby obtaining a steroid of formula.

CHzOR steroid having the formula,

0 CH,Og-CH1 No references cited.

CH CH:

CHgCwO

1. PROCESS WHICH COMPRISES REACTING A STEROID HAVING A RING D THESTRUCTURE,